Mechanisms regulating cell fate decisions during Drosophila Development

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Normal development requires the commitment of individual cells to an appropriate cell fate and subsequent differentiation. The long-term goal of my research program is to understand how individual cell fates are acquired during development. Towards this goal, we have been studying the role of the Notch signaling pathway, which functions to determine the fate of virtually every cell type in all complex animals through distinct mechanisms that include lateral inhibition and asymmetric cell division. We have studied the role of Notch during development of the peripheral nervous system in Drosophila where Notch initially specifies the fate of sensory organ precursor cells (SOPs) from a group of equipotent cells through lateral inhibition. Subsequently, Notch regulates the asymmetric cell division of SOPs ensuring that fate determinants are appropriately segregated into daughter cells thereby specifying their individual fates. A key component of the Notch signaling pathway that is required for both lateral inhibition and asymmetric cell division is Neuralized (Neur), which encodes an E3-ubiquitin ligase. We have shown that Neur plays an essential role in SOP fate determination by binding and ubiquitinating the Notch ligands, Delta & Serrate, leading to their endocytosis and Notch activation. Neur is also required for asymmetric cell divisions although it does not play a role in the segregation of cell fate determinants. Interestingly, we have recently found that Neur binds and co-localizes with Mushroom body defect (Mud) and Klaroid. Mud is a homolog of the mammalian protein Nuclear Mitotic Apparatus (NuMA), which regulates alignment of the mitotic spindle and is essential for asymmetric cell divisions. Klaroid encodes a SUN domain containing protein, which together with Mud/NuMA, regulate the integrity of the nuclear envelope and dynamic organization of chromosomes. We hypothesize that Neur plays an essential role in asymmetric cell division by regulating the activity of Mud/NuMA and Klaroid. To test this hypothesis, we will use a combination of in vitro and in vivo approaches to: 1. Characterize the interaction between Neur and Mud. 2. Determine how Neur affects Mud function. 3. Determine whether the interaction of Neur and Klar asymmetric cell division. Altogether, these experiments will reveal novel functions for Neur during asymmetric cell division. More importantly, these studies will provide insight into how lateral inhibition and asymmetric cell divisions are coordinated to specify cell fate decisions during development.